3&#39;-[(2z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4h-pyrazol-4-ylidene]hydrazino]-2&#39;-hydroxy-[1,1&#39;-biphenyl]-3-carboxylic acid bis-(monoethanolamine)

ABSTRACT

Disclosed are novel pharmaceutical compositions containing 3′-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene]hydrazinol-2′-hydroxy-[1,1′-biphenyl]-3-carboxylic acid bis-(monoethanolamine) (eltrombopag olamine) and processes for preparing the same.

FIELD OF THE INVENTION

The present invention relates to granules and solid oral pharmaceuticaldosage forms, suitably tablets, suitably capsules, comprising3′-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene]hydrazino]-2′-hydroxy-[1,1′-biphenyl]-3-carboxylicacid bis-(monoethanolamine) represented by the following formula (I) andhereinafter referred to as “eltrombopag olamine” or Compound B:

BACKGROUND OF THE INVENTION

3′-{N′[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene]hydrazino}-2′-hydroxybiphenyl-3-carboxylicacid (hereinafter Compound A) is a compound which is disclosed andclaimed, along with pharmaceutically acceptable salts, hydrates,solvates and esters thereof, as being useful as an agonist of the TPOreceptor, particularly in enhancing platelet production and particularlyin the treatment of thrombocytopenia, in International Application No.PCT/US01/16863, having an International filing date of May 24, 2001;International Publication Number WO 01/89457 and an InternationalPublication date of Nov. 29, 2001; which has United States PublicationNumber US2004/0019190 A1, having a United States Publication date ofJan. 29, 2004; now U.S. Pat. No. 7,160,870, issued Jan. 9, 2007, thedisclosure of which is hereby incorporated by reference.

The bis-(monoethanolamine) salt of this compound is disclosed (disclosedas3′-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene]hydrazino]-2′-hydroxy-[1,1′-biphenyl]-3-carboxylicacid, which also describes Compound A) in International Application No.PCT/US03/16255, having an International filing date of May 21, 2003;International Publication Number WO 03/098002 and an InternationalPublication date of Dec. 4, 2003; which has United States PublicationNumber US2006/0178518 A1, having a United States Publication date ofAug. 10, 2006; the disclosure of which is hereby incorporated byreference.

Compound A is disclosed for the treatment of degenerativediseases/injuries in International Application No. PCT/US04/013468,having an International filing date of Apr. 29, 2004; InternationalPublication Number WO 04/096154 and an International Publication date ofNov. 11, 2004; which has United States Publication Number US2007/0105824A1, having a United States Publication date of May 10, 2007; thedisclosure of which is hereby incorporated by reference.

Compositions that may contain Compound A and/or Compound B are disclosedin International Application No. PCT/US01/16863, InternationalApplication No. PCT/US03/16255 and International Application No.PCT/US04/013468.

Solid oral pharmaceutical dosage forms are popular and useful forms ofmedications for dispensing pharmaceutically active compounds. A varietyof such forms are known, including tablets, capsules, pellets, lozenges,and powders.

However, the formulation of an acceptable solid oral pharmaceuticaldosage form on a commercial scale is not always straightforward. Theformula and process of manufacture must be such as to provide anintegral solid dosage form that maintains its integrity until used. Thesolid dosage form must also possess acceptable dissolution anddisintegration properties so as to provide the desired profile in use.Pharmaceutically active compounds with low solubility and/or that canreact with commonly used excipients can present particular challenges inpreparing high quality solid dosage forms, since the physical propertiesof the drug influence the properties of the solid dosage form. Theformulator must balance the drug's unique properties with the propertiesof each excipient in order to prepare a safe, efficacious and easy touse solid dosage form.

Eltrombopag olamine presents the formulator with unique concerns whenattempting to formulate this compound into a suitable solid oralpharmaceutical dosage form, suitably a tablet, suitably a capsule, witha desirable pharmacokinetic profile, particularly on a commercial scale.Such concerns include, but are not limited to; the tendency of thecompound to form insoluble metal complexes when contacted withexcipients that contain a coordinating metal, slow dissolution of thecompound from solid dosage forms and the tendency of the compound tounder go a Maillard reaction when contacted with excipients that containreducing sugars. Significant realization of these concerns will have anadverse effect on the in vivo administration of eltrombopag olamine.

It would be desirable to provide eltrombopag olamine in a solid oralpharmaceutical dosage form on a commercial scale with a desirablepharmacokinetic profile.

The present invention is directed to granules and solid oralpharmaceutical dosage forms that contain eltrombopag olamine, suitablythe solid dosage form is a tablet, suitably the solid dosage form is acapsule, suitably these solid dosage forms are produced on a commercialscale.

SUMMARY OF THE INVENTION

The present invention relates to granules and solid oral pharmaceuticaldosage forms comprising a therapeutically effective amount ofeltrombopag olamine. The invention also relates to a process for makinggranules and solid oral pharmaceutical dosage forms comprisingeltrombopag olamine.

Another aspect of this invention relates to granules and solid oralpharmaceutical dosage forms, suitably tablets, suitably capsules,comprising eltrombopag olamine that are formulated using diluents thatare substantially free of reducing sugars, which as used herein and inthe claims includes diluents that are free of reducing sugars, and thatare substantially free of coordinating metals, which as used herein andin the claims includes diluents that are free of coordinating metals.Such granules and solid oral pharmaceutical dosage forms exhibitimproved properties. Such improved properties help to ensure safe andeffective treatment.

Another aspect of this invention relates to film coated pharmaceuticaltablets comprising eltrombopag olamine, wherein the film coat containsno coordinating metals, or only an amount of coordinating metalapproximately equal to or less than 0.025 parts of Compound B. Suchtablets exhibit improved properties. Such improved properties help toensure safe and effective treatment.

Another aspect of this invention relates to granules and solid oralpharmaceutical dosage forms comprising eltrombopag olamine that areformulated with a defined drug particle size range where about 90% ofdrug particle size is in the range of 10 to 90 microns. Such tabletsexhibit improved properties. Such improved properties help to ensuresafe and effective treatment.

Another aspect of this invention relates to granules and solid oralpharmaceutical dosage forms containing eltrombopag olamine comprising ahigh percentage of disintegrant, suitably an amount equal to or greaterthan 4%. Such tablets exhibit improved properties. Such improvedproperties help to ensure safe and effective treatment.

Another aspect of this invention relates to a method of treatingthrombocytopenia, which method comprises administering to a subject inneed thereof a therapeutically effective amount of granules or a solidoral pharmaceutical dosage form of the present invention.

Another aspect of this invention relates to a method of agonizing theTPO receptor, which method comprises administering to a subject in needthereof a therapeutically effective amount of granules or a solid oralpharmaceutical dosage form of the present invention.

Also included in the present invention are methods of co-administeringgranules or a solid oral pharmaceutical dosage form of the presentinvention with further active ingredients.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts the dissolution comparison of tablets containingeltrombopag and a metal containing diluent with tablets containingeltrombopag and a non-metal containing diluent.

FIG. 2 depicts the effect of API particle size on the dissolution ofeltrombopag from 75 mg tablets.

DETAILED DESCRIPTION OF THE INVENTION

By the term “coordinating metal” and “coordinating metals” andderivatives thereof, as used herein is meant a metal or a metalcontaining excipient, suitably a diluent, or metal containing tabletcoating material, which forms a complex, such as a chelate complex, inthe presence of eltrombopag olamine. Examples of such metals include:

-   -   aluminum, calcium, copper, cobalt, gold, iron, magnesium,        manganese and zinc.

By the term “reducing sugar” as used herein is meant a sugar or sugarcontaining excipient, suitably a diluent, which reacts with eltrombopagolamine to form a Maillard product when admixed together. Examples ofsuch reducing sugars include:

lactose, maltose, glucose, arabinose and fructose.

The term Maillard reaction is well known in the art and is utilizedherein as to its standard meaning. Generally, the term Maillard reactionis used herein to mean the reaction of a reducing sugar, as definedherein, in a formulation, suitably granules or solid dosage forms, witheltrombopag olamine that produces a pigment or pigments, suitably abrown pigment. The pigments are referred to herein as Maillard products.The production of such Maillard products is an indication of chemicalinstability.

As used herein, the term “improved properties” and derivatives thereof,contemplates several advantages to the pharmacokinetic profile of the invivo release of Compound B from a formulation, suitably granules or asolid oral pharmaceutical dosage form, that utilizes an aspect of thepresent invention when compared to a formulation that does not utilizethat aspect of the present invention, suitably the formulation isproduced on a commercial scale, and will vary depending on theparticular aspect of the invention being utilized. Examples of improvedproperties include: increased oral bioavailability, reduced formation ofinsoluble metal complexes, improved chemical stability, a consistentpharmacokinetic profile and a consistent dissolution rate.

As used herein, the term “drug” or “active ingredient” and derivativesthereof, means Compound B or eltrombopag olamine.

By the term “commercial scale” and derivatives thereof, as used hereinis meant, preparation of a batch scale greater than about 20 kg ofgranulation mix, suitably greater than 50 kg, suitably greater than 75kg or a batch size suitable to prepare at least about 50,000 tablets,suitably at least 75,000 tablets, suitably at least 100,000 tablets.

When indicating that the diluents for use herein and in the claims aresubstantially free of coordinating metals and/or that are substantiallyfree of reducing sugars, it is contemplated that minor amounts, forexample: about 5% or less, of the diluent component could contain acoordinating metal or metals and/or a reducing sugar or reducing sugars.In this aspect of the invention, it is believed that very minor amountsof coordinating metals and/or reducing sugars can be incorporated intothe diluent component without adversely effecting tablet performance.

The term “effective amount” and derivatives thereof, means that amountof a drug or active ingredient that will elicit the biological ormedical response of a tissue, system, animal or human that is beingsought, for instance, by a researcher or clinician. Furthermore, theterm “therapeutically effective amount” means any amount which, ascompared to a corresponding subject who has not received such amount,results in improved treatment, healing, prevention, or amelioration of adisease, disorder, or side effect, or a decrease in the rate ofadvancement of a disease or disorder. The term also includes within itsscope amounts effective to enhance normal physiological function.

As used herein, the term “formulation” and derivatives thereof, unlessotherwise defined refers to granules and/or solid oral pharmaceuticaldosage forms of the invention that contain eltrombopag olamine.

By the term “co-administering” and derivatives thereof as used herein ismeant either simultaneous administration or any manner of separatesequential administration of granules and/or a solid oral pharmaceuticaldosage form of the present invention and a further active ingredient oringredients, known to treat thrombocytopenia, includingchemotherapy-induced thrombocytopenia and bone marrow transplantationand other conditions with depressed platelet production. The termfurther active ingredient or ingredients, as used herein, includes anycompound or therapeutic agent known to or that demonstrates advantageousproperties when administered with TPO or a TPO mimetic. Preferably, ifthe administration is not simultaneous, the compounds are administeredin a close time proximity to each other. Furthermore, it does not matterif the compounds are administered in the same dosage form, e.g. onecompound may be administered topically and another compound may beadministered orally.

Examples of a further active ingredient or ingredients for use incombination with the presently invented formulations include but are notlimited to: chemoprotective or myeloprotective agents such as G-CSF,BB10010 (Clemons et al., Breast Cancer Res. Treatment, 1999, 57, 127),amifostine (Ethyol) (Fetscher et al., Current Opinion in Hemat., 2000,7, 255-60), SCF, IL-11, MCP-4, IL-1-beta, AcSDKP (Gaudron et al., StemCells, 1999, 17, 100-6), TNF-α, TGF-b, MIP-1a (Egger et al., Bone MarrowTranspl., 1998, 22 (Suppl. 2), 34-35), and other molecules identified ashaving anti-apoptotic, survival or proliferative properties.

By the term “granules” and derivatives thereof, as used herein refers toformulated particles that comprise eltrombopag olamine, diluents thatare substantially free of coordinating metals and/or that aresubstantially free of reducing sugars, and suitably also binders and/orlubricants and/or disintegrants such that the particles are suitable forutilization in preparing solid oral pharmaceutical dosage forms. It isalso possible to administer the granules directly to a subject in needthereof as a medicament. However, it is anticipated that the granulesare most appropriately utilized in the preparation of solid oralpharmaceutical dosage forms as indicated above.

By the term “solid oral pharmaceutical dosage form” and “solid dosageform” and derivatives thereof, as used herein refers to a finalpharmaceutical preparation that comprises eltrombopag olamine, suchtablets, capsules, pellets, lozenges and powders (including coatedversions of any of such preparations) that are suitable for in vivoadministration.

Suitably, the granules and solid oral pharmaceutical dosage forms of thepresent invention comprise eltrombopag olamine, a diluent (also known asfiller or bulking agent), and suitably also a binder and/or a lubricantand/or a disintegrant. Those skilled in the art will recognize that agiven material may provide one or more functions in the tabletformulation, although the material is usually included for a primaryfunction. The percentages of diluent, binder, lubricant and disintegrantprovided herein and in the claims are by weight of the tablet.

Diluents provide bulk, for example, in order to make the tablet apractical size for processing. Diluents may also aid processing, forexample, by providing improved physical properties such as flow,compressibility, and tablet hardness. Because of the relatively highpercentage of diluent and the amount of direct contact between thediluent and the active compound in the typical pharmaceuticalformulation, the interaction of the diluent with the active compound isof particular concern to the formulator. Examples of diluents suitablefor general use include: water-soluble fillers and water-insolublefillers, such as calcium phosphate (e.g., di and tri basic, hydrated oranhydrous), calcium sulfate, calcium carbonate, magnesium carbonate,kaolin, spray dried or anhydrous lactose, cellulose (e.g.,microcrystalline cellulose, powdered cellulose), pregelatinized starch,starch, lactitol, mannitol, sorbitol, maltodextrin, powdered sugar,compressible sugar, sucrose, dextrose, and inositol. The diluents thatdo not contain coordinating metals and diluents that are non-reducingsugars are suitable for tablets of the current invention. Suitablediluents for use in this invention include microcrystalline cellulose,powdered cellulose, pregelatinized starch, starch, lactitol, mannitol,sorbitol, and maltodextrin. Unsuitable diluents include calciumphosphate (e.g., di and tri basic, hydrated or anhydrous), calciumsulfate, calcium carbonate, magnesium carbonate, kaolin, and spray driedor anhydrous lactose. In one embodiment of the present invention, thediluent is composed of one or both of Mannitol and microcrystallinecellulose.

The granules and solid oral pharmaceutical dosage forms of the presentinvention typically comprise from about 25% to about 89%, of one or morediluents.

One aspect of the present invention comprises granules wherein thegranules are formulated using a diluent or diluents that aresubstantially free of coordinating metals and/or that are substantiallyfree of reducing sugars.

One aspect of the present invention comprises solid oral pharmaceuticaldosage forms wherein the solid dosage forms are formulated using adiluent or diluents that are substantially free of coordinating metalsand/or that are substantially free of reducing sugars.

One aspect of the present invention comprises pharmaceutical tablets,wherein the tablets are formulated using a diluent or diluents that aresubstantially free of coordinating metals and/or that are substantiallyfree of reducing sugars.

One aspect of the present invention comprises pharmaceutical capsules,wherein the capsules are formulated using a diluent or diluents that aresubstantially free of coordinating metals and/or that are substantiallyfree of reducing sugars.

Binders impart cohesive properties to the powdered material. Examples ofbinders suitable for use in the present invention include: starch (e.g.,paste, pregelatinized, mucilage), gelatin, sugars (e.g., sucrose,glucose, dextrose, molasses, lactose, dextrin, xylitol, sorbitol),polymethacrylates, natural and synthetic gums (e.g., acacia, alginicacids and salts thereof such as sodium alginate, gum tragacanth, Irishmoss extract, panwar gum, ghatti gum, guar gum, zein), cellulosederivatives [such as carboxymethyl cellulose and salts thereof, methylcellulose (MC), hydroxypropyl methyl cellulose (HPMC), hydroxypropylcellulose (HPC), hydroxyethyl cellulose (HEC) and ethyl cellulose (EC)],polyvinylpyrrolidone, Veegum, larch arabogalactan, polyethylene glycol,waxes, water, alcohol, magnesium aluminum silicate, and bentonites. Inone embodiment of the present invention, the binder comprisespolyvinylpyrrolidone (PVP).

The granules and solid oral pharmaceutical dosage forms of the presentinvention typically comprise up to about 8% binder. The formulationssuitably comprise up to about 5%, suitably up to about 2% binder.

Lubricants are generally used to enhance processing, for example, toprevent adhesion of the formulation material to manufacturing equipment,reduce interparticle friction, improve rate of flow of the formulation,and/or assist ejection of the formulations from the manufacturingequipment. Examples of lubricants suitable for use in the presentinvention include: talc, stearates (e.g., magnesium stearate, calciumstearate, zinc stearate, palmitostearate), stearic acid, hydrogenatedvegetable oils, glyceryl behanate, polyethylene glycol, ethylene oxidepolymers (e.g., CARBOWAXes), liquid paraffin, sodium lauryl sulfate,magnesium lauryl sulfate, sodium oleate, sodium stearyl fumarate,DL-leucine, and silica derivatives (e.g., colloidal silicon dioxide,colloidal silica, pyrogenic silica, and hydrated sodiumsilicoaluminate). In one embodiment of the present invention, thelubricant comprises magnesium stearate.

The granules and solid oral pharmaceutical dosage forms of the presentinvention typically comprise up to about 2% lubricant. The formulationssuitably comprise up to about 1.5%, suitably up to about 1% lubricant.

Disintegrants are employed to facilitate breakup or disintegration ofthe formulation after administration. Examples of disintegrants suitablefor use in the present invention include: starches, celluloses, gums,crosslinked polymers, and effervescent agents, such as corn starch,potato starch, pregelatinized starch, modified corn starch,croscarmellose sodium, crospovidone, sodium starch glycolate, Veegum HV,methyl cellulose, microcrystalline cellulose, cellulose, modifiedcellulose gum (e.g., Ac-Di-Sol R), agar, bentonite, montmorilloniteclay, natural sponge, cation exchange resins, ion exchange resins (e.g.,polyacrin potassium), alginic acid and alginates, guar gum, citrus pulp,carboxymethylcellulose and salts thereof such as sodium lauryl sulfate,magnesium aluminum silicate, hydrous aluminum silicate, sodiumbicarbonate in admixture with an acidulant such as tartaric acid orcitric acid. In one embodiment of the present invention, thedisintegrant is sodium starch glycolate.

The granules and solid oral pharmaceutical dosage forms of the presentinvention typically comprise an amount from 4% to about 12%disintegrant. The formulations suitably comprise from about 6% to about10%, suitably from about 7% to 9% disintegrant.

The solid oral pharmaceutical dosage forms, suitably tablets, suitablycapsules, of the present invention will typically be sized up to 1 gram,e.g., from about 0.01 gram to about 0.8 gram. These solid dosage formstypically comprise from about 5 mg to about 900 mg of eltrombopagolamine per dosage form. In suitable embodiments, the solid dosage formscomprise from about 5 to about 200 mg eltrombopag olamine (e.g., in anabout 100-800 mg dosage form). Tablet formulations of the invention mayhave a variety of shapes, including diamond, modified capsule, modifiedoval, and hexagonal, and may optionally have a tilt.

Tablets

The choice of particular types and amounts of excipients, and tablettingtechnique employed depends on the further properties of eltrombopagolamine and the excipients, e.g., compressibility, flowability, particlesize, compatibility, and density. The tablets may be prepared accordingto methods known in the art, including direct compression, drygranulation, fluid bed granulation, and wet granulation, and the type ofexcipients used will vary accordingly. It has been found that wetgranulation is particularly suitable for providing high strength, lowbreakage tablets comprising relatively high concentrations ofeltrombopag olamine (e.g., about 40% or more), on a scale suitable forcommercial production. Suitable wet granulated tablets of the inventioncomprise granules comprising eltrombopag olamine and one or more offillers, binders and disintegrants, wherein the granules are mixed withadditional filler, binder, disintegrant and/or lubricant to form acompression mixture that is compressed to form tablets.

Included in the present invention are pharmaceutical compositions intablet form, suitably prepared on a commercial scale, that compriseeltrombopag olamine, wherein the tablet is made by a wet granulationprocess using a diluent or diluents that are substantially free ofcoordinating metals and/or that are substantially free of reducingsugars. Also included in the present invention are such pharmaceuticalcompositions that contain a film coat, wherein the film coat contains nocoordinating metals, or only an amount of coordinating metalapproximately equal to or less than 0.025 parts of Compound B.

Also included in the present invention are pharmaceutical compositionsthat comprise eltrombopag olamine, wherein the tablet is made by a wetgranulation process, suitably on a commercial scale, using a diluent ordiluents that are substantially free of coordinating metals and/or thatare substantially free of reducing sugars, and about 90% of theeltrombopag olamine particles have a particle size greater than 10micron but less than 90 micron.

Also included in the present invention are pharmaceutical compositionsthat comprise eltrombopag olamine, wherein the tablet is made by a wetgranulation process, suitably on a commercial scale, using a diluent ordiluents that are substantially free of coordinating metals and/or thatare substantially free of reducing sugars, and about 90% of theeltrombopag olamine particles have a particle size greater than 10micron but less than 90 micron, suitably greater than 20 micron but lessthan 50 micron.

Also included in the present invention are pharmaceutical compositionsthat comprise eltrombopag olamine, wherein the tablet is made by a wetgranulation process, suitably on a commercial scale, using a diluent ordiluents that are substantially free of coordinating metals and/or thatare substantially free of reducing sugars, and about 50% of theeltrombopag olamine particles have a particle size greater than 5 micronbut less than 50 micron, suitably greater than 5 micron but less than 20micron.

In one embodiment of the present invention, the tablets of the presentinvention comprise:

-   -   (i) from about 2% to about 65% eltrombopag olamine;    -   (ii) from about 25% to about 89% of diluent;    -   (iii) up to about 8% binder, suitably up to about 5%, suitably        up to about 4%;    -   (iv) up to about 2% lubricant, suitably up to about 1.5%,        suitably up to about 1%; and    -   (v) from 4% to about 12% disintegrant, suitably 6% to 10%,        suitably from 7% to 9%.

Suitable wet granulated tablets comprise, by weight of the tablet, fromabout 10% to about 95% of eltrombopag olamine active intragranules andfrom about 5% to about 90% of external excipients; wherein theeltrombopag olamine active intragranules comprise, by weight of theintragranules:

-   -   (i) from about 2% to about 88% eltrombopag olamine;    -   (ii) from about 10% to about 96% diluent;    -   (iii) from about 2% to about 5% binder; and    -   (iv) optionally from 0% to about 4% disintegrant;        and wherein the external excipients comprise, by weight of the        tablet:    -   (i) from 0% to about 70% diluent;    -   (ii) from about 0.25% to about 2%, suitably from about 0.25% to        about 1.25% lubricant; and    -   (iii) from 4% to about 10% disintegrant.

In the foregoing embodiments, the diluent is suitably a combination ofmannitol and microcrystalline cellulose, the non-reducing sugar issuitably mannitol, the binder is suitably polyvinylpyrolidone, thelubricant is suitably magnesium stearate, and the disintegrant issuitably sodium starch glycolate. Suitably, the intragranule filler is amixture of mannitol and microcrystalline cellulose and the externalfiller is microcrystalline cellulose.

In one embodiment of the current invention, tablets are coated with afilm coat formed from an aqueous film coat composition. Aqueous filmcoat compositions suitable for use in the present invention comprise afilm-forming polymer, water as a vehicle, and optionally one or moreadjuvants such as are known in the film-coating art. When the film coatcontains a coordinating metal, as used herein, the amount ofcoordinating metal is approximately equal to or less than 0.025 parts ofCompound B.

The film-forming polymer is selected to form coatings with mechanicalproperties (e.g., mechanical strength, flexibility) suitable to meetperformance requirements, such as those required by the intended useenvironment (e.g., dissolution profile in gastrointestinal fluids),and/or use (e.g. solution viscosity). Examples of suitable film-formingpolymers include cellulosic polymers (e.g., cellulose ethers such asHPMC, HPC, MC, EC, HEC, CAP, sodium ethyl cellulose sulfate,carboxymethyl cellulose and the like); polyvinylpyrolidone; zein; andacrylic polymers (e.g., methacrylic acid/methacrylic acid estercopolymers such as methacrylic acid/methylmethacrylate copolymers andthe like). Cellulosic polymers are preferred in the present invention,especially cellulosic ethers and more especially HPMC and HPC. Thepolymers are typically provided in either aqueous or organic solventbased solutions or aqueous dispersions. However, the polymers may beprovided in dry form, alone or in a powdery mixture with othercomponents (e.g., a plasticizer and/or colorant), which is made into asolution or dispersion by the user by admixing with the aqueous vehicle.

The aqueous film coat composition further comprises water as a vehiclefor the other components, to facilitate their delivery to the tabletsurface. The vehicle may optionally further comprise one or more watersoluble solvents, e.g., alcohols (e.g., methanol, isopropanol, propanol)and ketones (e.g., acetone). The skilled artisan can select appropriatevehicle components to provide good interaction between the film-formingpolymer and the vehicle to ensure good film properties. In general,polymer—vehicle interaction is designed to yield maximum polymer chainextension to produce films having the greatest cohesive strength andthus mechanical properties. The components are also selected to providegood deposition of the film-forming polymer onto the tablet surface,such that a coherent and adherent film is achieved.

The aqueous film coating composition may optionally comprise one or moreadjuvants known in the art, such as plasticizers, colorants,detackifiers, secondary film-forming polymers, flow aids, surfactants(e.g., to assist spreading), maltodextrin, and polydextrose.

Plasticizers provide flexibility to the film, which may reduce filmcracking and improve adhesion to the tablet. Suitable plasticizers willgenerally have a high degree of compatibility with the film-formingpolymer and sufficient permanence such that the coating properties aregenerally stable. Examples of suitable plasticizers include glycerin,propylene glycol, polyethylene glycols (e.g., molecular weight from 200to 20,000, including Union Carbide's PEG 400, 4000, 6000, 8000, and20,000), glycerin triacetate (aka triacetin), acetylated monoglyceride,citrate esters (e.g., triethyl citrate, acetyl triethyl citrate,tributyl citrate, acetyl tributyl citrate), phthalate esters (e.g.,diethyl phthalate), mineral oil and hydrogenated glucose syrup. In oneembodiment of the present invention, the plasticizer is chosen frompolyethylene glycols, triacetin, propylene glycol, glycerin, andmixtures thereof

The aqueous film coat composition suitably comprises one or morecolorants. In addition to enhancing esthetic appeal, the colorantprovides product identification. Suitable colorants include thoseapproved and certified by the FDA, including FD&C and D&C approved dyes,lakes, and pigments, and titanium dioxide, provided that the film coatcontains no coordinating metals, or only an amount of coordinating metalapproximately equal to or less than 0.025 parts of Compound B.

Suitably, the colorant comprises one or more coloring agents selectedfrom the group consisting of red iron oxides, red dyes and lakes, yellowiron oxides, yellow dyes and lakes, titanium dioxide, and indigocarmine. For example, the colorant may be selected to provide a lightbeige shade, for example consisting essentially of a) red iron oxide,red dye, and/or red lake, b) yellow iron oxide, yellow dye, and/oryellow lake, and c) titanium dioxide. Alternatively, the colorant may beselected to provide a pink shade (e.g., consisting essentially oftitanium dioxide and red iron oxide, red dye and/or red lake); a lightgreen shade (e.g., consisting essentially of yellow iron oxide, yellowdye and/or yellow lake, indigo carmine, and titanium dioxide); a lightblue shade (e.g., consisting essentially of titanium dioxide and indigocarmine); or an orange shade (e.g., consisting of essentially oftitanium dioxide and sunset yellow).

The above mentioned colorants that contain a coordinating metal areacceptable at a level approximately equal to or less than 0.025 parts ofCompound B.

In suitable alternative embodiments, the aqueous film coatingcomposition for use in the current invention comprises:

-   -   a cellulosic film-forming polymer; and    -   (ii) a plasticizer.

Suitably, such compositions further comprise a colorant. Suchcompositions may optionally further comprise one or more additionaladjuvants such as a detackifier, flow aid, surfactant, and secondaryfilm-forming polymer.

Examples of optional detackifiers include lecithin, stearic acid,mineral oil, modified derivatized starch, tapioca dextrin, andpolyethylene glycol. Examples of optional secondary film-formingpolymers include sodium alginate, propylene glycol alginate, andpolyvinylpyrrolidone. Examples of optional surfactants include dioctylsodium sulfosuccinate and polysorbate 80. Examples of optional flow aidsinclude talc, fumed silica, bentonite, hydrogenated vegetable oils,stearines, and waxes.

The aqueous film coat composition will typically comprise from about 5%to about 25%, suitably about 5% to about 20%, coating solids in thevehicle. In suitable embodiments, the solids typically comprise fromabout 25% to about 70%, suitably about 60% to about 70% film-formingpolymer, about 5% to about 10%, suitably about 6% to about 8%,plasticizer, and about 20% to about 35% colorant, by weight.

A number of suitable aqueous film coating compositions are commerciallyavailable. The aqueous film coat composition may be provided in the formof a solution or dispersion. Alternatively, the composition may beprovided in a dry form that can be combined with the vehicle componentsaccording to supplier instructions prior to coating the tablet.Suitably, aqueous film coating compositions are those commerciallyavailable from Colorcon, Inc. of West Point, Pa., under the trade nameOPADRY and OPADRY II (nonlimiting examples include Opadry YS-1-7706-Gwhite, Opadry Yellow 03B92357, Opadry Blue 03B90842). These compositionsare available as dry film coating compositions that can be diluted inwater shortly before use. OPADRY and OPADRY II formulations comprise acellulosic film forming polymer (e.g., HPMC and/or HPC), and may containpolydextrose, maltodextrin, a plasticizer (e.g., triacetin, polyethyleneglycol), polysorbate 80, a colorant (e.g., titanium dioxide, one or moredyes or lakes), and/or other suitable film-forming polymers (e.g.,acrylate-methacrylate copolymers). Suitable OPADRY or OPADRY IIformulations may comprise a plasticizer and one or more of maltodextrin,and polydextrose (including but not limited to a) triacetin andpolydextrose or maltodextrin or lactose, or b) polyethylene glycol andpolydextrose or maltodextrin).

The tablets are also suitably coated to provide a uniform coatingwithout speckling. The tablets are typically coated to provide a drytablet weight gain of from about 2 to about 5%, suitably about 3 to 4%.

The uncoated tablet cores are coated with the aqueous film coatingcomposition by methods well known in the art using commerciallyavailable equipment (e.g., Thomas Accela-Cota, Vector Hi-Coater,Compu-Lab 36). In general, the process usually involves rolling ortumbling the tablets in a pan, or suspending the tablets on a cushion ofair (fluidized bed), and intermittently or continuously (preferablycontinuously) spraying a fine mist of atomized droplets of the coatingcomposition onto the tablets, the droplets wetting, spreading andcoalescing on the surface of the tablets to form an adherent andcoherent film coating. The tablets are typically heated to about 40 to50° C., suitably about 45 to 50° C., e.g., by air having a temperatureof up to about 75° C., suitably about 65 to 70° C.

Process of Making the Tablet

Pharmaceutical tablets of the invention that are wet-granulated can beprepared by a process comprising the steps of:

I) preparing the granules; which comprises the steps of:

-   -   a) mixing together the dry materials comprising eltrombopag        olamine, a diluent, a binder, and optionally a disintegrant for        a time sufficient to homogenize the materials;    -   b) adding a granulating fluid to the mixture of dry materials,        preferably while mixing;    -   c) mixing the granulating fluid with the mixture of dry        materials for a granulating time sufficient to generally        uniformly wet the dry materials, so as to form wet granules;    -   d) wet-milling the wet granules;    -   e) drying the wet-milled granules to form dry granules; and    -   f) dry milling the dry granules to form granules of desired        size;        II) preparing the tablet; which comprises the steps of:    -   a) mixing the granules prepared in step I) f) with external        excipients comprising a filler, a lubricant and a disintegrant        for a time sufficient to homogenize the granules and external        excipients; and    -   b) compressing the mixture comprising the granules and external        excipients to form a tablet.

Suitably, the tablets are further film-coated, especially aqueousfilm-coated.

In preparing wet-granulated granules, the dry materials may be mixedwith suitable equipment such as known in the art (e.g., Niro-FielderBlender/Granulator, Bear Varimixer, Key High Shear Mixer/Granulator) fora time sufficient to homogenize the materials, e.g., for about 3minutes.

The granulating fluid is then added to the dry mixture, preferably whilemixing. The granulating fluid is suitably water, although mayalternatively be comprised of water in admixture with one or more ofbinders such as PVP and HPMC, from about 10 v/w % to about 30 v/w % ofthe granulating fluid, based on the total wet granulation mixture, issuitably used. The granulating fluid and dry materials may be mixedusing suitable equipment such as known in the art (e.g., Niro-FielderBlender/Granulator, Bear Varimixer, Key High Shear Mixer/Granulator) fora total time sufficient to generally uniformly wet the dry material soas to form wet granules, suitably for about 3 to about 15 minutes.Typically the fluid is added to the dry material with mixing over aperiod of about 1 to about 15 minutes, then the total batch is mixed foran additional time (post-granulating fluid-addition time), of about 0.5minutes to about 6 minutes.

In a suitable embodiment, about 10 v/w % to about 30 v/w % granulatingfluid and a post-granulating fluid-addition granulating time of about 6minutes or less is used. Suitably, about 24 v/w % granulating fluid anda post-granulating fluid-addition granulating time of less than 3minutes is used, e.g., about 2.5 minutes. Suitably, about 16 v/w %granulating fluid and a post-granulating fluid-addition granulating timeof more than 2.5 minutes is used, e.g., about 4 minutes.

The wet granules are then wet-milled by methods such as are known in theart for providing a generally uniformly sized wet mass (such that thegranules dry relatively evenly). Suitable wet-milling techniques mayinvolve screening (e.g., manual screens), comminuting mills (such as aCo-mil, including but not limited to a 0.375″ screen), or extruders.

The wet-milled granules are dried by methods such as are known in theart for providing generally uniform drying, to a low residual amount ofgranulating fluid (preferably about 0.5% to about 1.0%). Fluid beddryers are suitable drying equipment.

The dried granules are then dry-milled using known methods to providegenerally uniformly sized granules (unimodal distribution), suitablyhaving a mean particle diameter of less than 240 microns (found toprovide improved content uniformity). Suitable dry-milling equipmentincludes Co-mils, including but not limited to having a 0.094″ screen.

Suitably the granules and the dry materials of the compression mix aregenerally unimodal in size distribution, in order to facilitateformation of a homogeneous mix and to mitigate possible segregation ofthe mix after blending. If necessary, the dry materials may bepre-screened to provide the desired particle size distribution.Screening of the lubricant may be particularly useful to deagglomeratethe lubricant.

In preparing the compression mixture, the granules, filler, anddisintegrant are mixed over a suitable period of time, about 5 to 15minutes. Lubricant is then added and mixed for a suitable period oftime, about 1 to 4 minutes. The mixture is then compressed into tabletsusing presses such as are known in the art (e.g., rotary tablet press).

It has been found that the above granulating fluid levels, granulatingtimes, and excipients provide improved processing.

Capsules

The choice of particular types and amounts of excipients, andcapsulation technique employed depends on the further properties ofeltrombopag olamine and the excipients, e.g., compressibility,flowability, particle size, compatibility, and density. The capsules maybe prepared according to methods known in the art, suitably filling astandard two piece hard gelatin capsule with eltrombopag olamine admixedwith excipients, suitably filling a standard two piece hard gelatincapsule with granules prepared according to this invention, suitably ona scale suitable for commercial production. Suitable capsules of theinvention comprise granules comprising eltrombopag olamine and one ormore of fillers, binders and disintegrants, wherein the granules aremixed with additional filler, binder, disintegrant and/or lubricant toform a granular mixture that is filled into capsules.

Included in the present invention are pharmaceutical compositions incapsule form, suitably prepared on a commercial scale, that compriseeltrombopag olamine, wherein the capsule is made using a diluent ordiluents that are substantially free of coordinating metals and/or thatare substantially free of reducing sugars.

Also included in the present invention are pharmaceutical compositionsthat comprise eltrombopag olamine, wherein the capsule is made, suitablyon a commercial scale, using a diluent or diluents that aresubstantially free of coordinating metals and/or that are substantiallyfree of reducing sugars, and about 90% of the eltrombopag olamineparticles have a particle size greater than 10 micron but less than 90micron.

Also included in the present invention are pharmaceutical compositionsthat comprise eltrombopag olamine, wherein the capsule is made, suitablyon a commercial scale, using a diluent or diluents that aresubstantially free of coordinating metals and/or that are substantiallyfree of reducing sugars, and about 90% of the eltrombopag olamineparticles have a particle size greater than 10 micron but less than 90micron, suitably greater than 20 micron but less than 50 micron.

Also included in the present invention are pharmaceutical compositionsthat comprise eltrombopag olamine, wherein the capsule is made, suitablyon a commercial scale, using a diluent or diluents that aresubstantially free of coordinating metals and/or that are substantiallyfree of reducing sugars, and about 50% of the eltrombopag olamineparticles have a particle size greater than 5 micron but less than 50micron, suitably greater than 5 micron but less than 20 micron.

The invented granules and solid oral pharmaceutical dosage forms may beadministered in therapeutically effective amounts to treat or prevent adisease state, e.g., as described in the above referenced InternationalApplications Nos. PCT/US01/16863, PCT/US03/16255 and PCT/US04/013468,the disclosures of which are herein incorporated by reference. It willbe recognized by one of skill in the art that the optimal quantity andspacing of individual dosages of eltrombopag olamine formulations of theinvention will be determined by the nature and extent of the conditionbeing treated and the particular patient being treated, and that suchoptimums can be determined by conventional techniques. It will also beappreciated by one of skill in the art that the optimal course oftreatment, i.e., the number of doses of eltrombopag olamine given perday for a defined number of days, can be ascertained by those skilled inthe art using conventional course of treatment determination tests.

A method of this invention of inducing TPO agonist activity in humanscomprises administering to a subject in need of such activity atherapeutically effective amount of a solid oral pharmaceutical dosageform of the present invention.

The invention also provides for the use of eltrombopag olamine in themanufacture of a solid oral pharmaceutical dosage form of the presentinvention.

The invention also provides for the use of eltrombopag olamine in themanufacture of a solid oral pharmaceutical dosage form of the presentinvention for use in enhancing platelet production.

The invention also provides for the use of eltrombopag olamine in themanufacture of a solid oral pharmaceutical dosage form of the presentinvention for use in treating thrombocytopenia.

The invention also provides for a solid oral pharmaceutical dosage formfor use as a TPO mimetic which comprises eltrombopag olamine and apharmaceutically acceptable carrier of the present invention.

The invention also provides for a solid oral pharmaceutical dosage formfor use in the treatment of thrombocytopenia which comprises eltrombopagolamine and a pharmaceutically acceptable carrier of the presentinvention.

The invention also provides for a solid oral pharmaceutical dosage formfor use in enhancing platelet production which comprises eltrombopagolamine and a pharmaceutically acceptable carrier of the presentinvention.

The invention also provides a process for preparing solid oralpharmaceutical dosage forms containing a diluent or diluents that aresubstantially free of coordinating metals and/or that are substantiallyfree of reducing sugars and a therapeutically effective amount ofeltrombopag olamine, which process comprises bringing eltrombopagolamine into association with the diluent or diluents.

No unacceptable toxicological effects are expected when the compound ofthe invention is administered in accordance with the present invention.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following Examples, therefore, are to beconstrued as merely illustrative and not a limitation of the scope ofthe present invention.

All the excipients utilized herein are standard pharmaceutical gradeexcipients available from numerous manufacturers well known to those inthe art.

EXAMPLES Examples 1 to 7 Tablet Preparation

Wet granulated, tablets comprising eltrombopag olamine and theingredients in Table 1 were prepared.

TABLE 1 Tablet Strength Component 12.5 mg 25 mg 25 mg 50 mg 50 mg 75 mg100 mg Granules 40% Drug-loaded (39.9) (79.7) (79.7) (159.4) (159.4)(239.1) (318.8) eltrombopag olamine, milled 15.95 31.9 31.9 63.8 63.895.7 127.6 Microcrystalline cellulose 7.45 14.9 14.9 29.8 29.8 44.7 59.6Mannitol 14.9 29.7 29.7 59.5 59.5 89.2 118.9 Povidone 1.6 3.2 3.2 6.46.4 9.6 12.8 Purified water — — — — Extra-granular componentsMicrocrystalline cellulose 119.4 238.8 238.8 159.1 159.1 79.3 NA Sodiumstarch glycolate 14.0 28.0 28.0 28.0 28.0 28.0 27.6 Magnesium Stearate1.75 3.5 3.5 3.5 3.5 3.5 3.5 Film-coating components Purified water — —— — Opacity ® white 8.9 14.0 14.0 14.0 Opadry Orange 14.0 Opadry Brown14.0 Opadry Blue 14.0 Total tablet weight (mg/tablet) 183.9 364 364 364364 364 364

Granules were prepared by separately weighing and screening mannitol,microcrystalline cellulose and povidone.

As a general procedure, the ingredients were blended with the activeingredient and then wet-granulated (in a high-shear wet-granulator) withpurified water. The wet-granule mass was wet-milled, then dried in afluid-bed dryer and the dried granules were milled.

Then extragranular ingredients (microcrystalline cellulose, if needed,and sodium starch glycolate) were separately weighed, screened andblended with the granules. Magnesium stearate was added and blended withthe mixture. The blend was compressed and the tablet cores were thenfilm coated. The tablets were film coated with an aqueous suspension ofOPADRY film coating preparation.

Example 8 Tablet Preparation

Eltrombopag olamine tablets containing diluents with the coordinatingmetal calcium phosphate dibasic anhydrous were manufactured in a similarmanner as described above. Tablet composition for the tabletcoordinating metal diluent is provided in table 2.

TABLE 2 Tablet Strength Component 50 mg Granules 40% Drug-loaded (159.4)eltrombopag olamine, milled 63.8 Calcium Phopshate dibasic anhydrous89.3 Povidone 6.4 Purified water — Extra-granular componentsMicrocrystalline cellulose 159.1 Sodium starch glycolate 28.0 MagnesiumStearate 3.5 Film-coating components Purified water — Opadry ® white14.0 Total tablet weight (mg/tablet) 364

In FIG. 1, the tablet prepared with no coordinating metal diluent(indicated as “with non-coordinating metal diluent”) is a eltrombopag 50mg tablet generally prepared as described in Table 1 above and thetablet prepared with the coordinating metal diluent—Calcium Phopshatedibasic anhydrous—(indicated as “with coordinating metal diluent”) is aeltrombopag 50 mg tablet generally prepared as described in Table 2above. Dissolution comparison was performed using USP Apparatus II, 50rpm, in phosphate buffer pH 6.8 containing 0.5% Tween 80.

Example 9

FIG. 2 depicts the effect of API particle size distribution oneltrombopag olamine dissolution. Eltrombopag olamine 75 mg tablets weregenerally prepared in the manner described in Example 5, using differentparticle sizes. The particle size refers to the particle size of thedrug granules used in the formulation.

Dissolution comparison was performed using USP Apparatus II, 50 rpm, inphosphate buffer pH 6.8 containing 0.5% Tween 80.

What is claimed is:
 1. The pharmaceutical tablet comprising: a) a drug,which is3′-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene]hydrazino]-2′-hydroxy-[1,1′-biphenyl]-3-carboxylicacid bis-(monoethanolamine); wherein, b) 90% of the drug particles havea particle size greater than 10 micron but less than 90 micron.
 2. Amethod of treating thrombocytopenia in a human in need thereof whichcomprises administering to such human a therapeutically effective amountof a pharmaceutical tablet according to claim
 1. 3. A process forpreparing pharmaceutical tablets containing the compound of claim 1,which process comprises the steps of; a) admixing: the compound3′-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene]hydrazino]-2′-hydroxy-[1,1′-biphenyl]-3-carboxylicacid bis-(monoethanolamine), wherein 90% of the compound particles havea particle size of greater than 10 micron but less than 90 micron; andone or more excipients; to form a mixture; and b) compressing themixture into tablets.
 4. The pharmaceutical tablet comprising: a) adrug, which is3′-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene]hydrazino]-2′-hydroxy-[1,1′-biphenyl]-3-carboxylicacid bis-(monoethanolamine); wherein, b) 90% of the drug particles havea particle size greater than 20 micron but less than 50 micron.
 5. Amethod of treating thrombocytopenia in a human in need thereof whichcomprises administering to such human a therapeutically effective amountof a pharmaceutical tablet according to claim
 4. 6. A process forpreparing pharmaceutical tablets containing the compound of claim 4,which process comprises the steps of; a) admixing: the compound3′-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene]hydrazino]-2′-hydroxy-[1,1′-biphenyl]-3-carboxylicacid bis-(monoethanolamine), wherein 90% of the drug particles have aparticle size greater than 20 micron but less than 50 micron; and one ormore excipients; to form a mixture; and b) compressing the mixture intotablets.
 7. The pharmaceutical tablet comprising: a) a drug, which is3′-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene]hydrazino]-2′-hydroxy-[1,1′-biphenyl]-3-carboxylicacid bis-(monoethanolamine); wherein, b) 50% of the drug particles havea particle size greater than 5 micron but less than 50 micron.
 8. Amethod of treating thrombocytopenia in a human in need thereof whichcomprises administering to such human a therapeutically effective amountof a pharmaceutical tablet according to claim
 7. 9. A process forpreparing pharmaceutical tablets containing the compound of claim 7,which process comprises the steps of; a) admixing: the compound3′-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene]hydrazino]-2′-hydroxy-[1,1′-biphenyl]-3-carboxylicacid bis-(monoethanolamine), wherein 50% of the drug particles have aparticle size greater than 5 micron but less than 50 micron; and one ormore excipients; to form a mixture; and b) compressing the mixture intotablets.